1. Field of the Invention
This invention relates to the controlled release of drugs. More particularly, this invention relates to polymeric devices for releasing a drug at a controlled rate over a prolonged period of time. This invention especially relates to improvements in rate-controlled drug release systems through the use of a particular polymeric material.
2. Description of the Prior Art
Polymeric devices for the controlled release of drugs are well known in the art. A common structure employed involves a polymer film or layer surrounding a reservoir containing a drug which may be in the form of a solution or dispersed in a matrix material. The drug diffuses through the polymer film at a controlled rate over a period of time. Many of the prior art devices and systems are said to release the drug at a rate which does not vary with time (see, for example, Higuchi, et al. U.S. Pat. No. 3,710,795 and Baker, et al. U.S. Pat. No. 3,926,188). A wide variety of polymeric materials have been employed in these drug release devices. Baker, et al. U.S. Pat. No. 3,926,188; Zaffaroni U.S. Pat. Nos. 3,993,072 and 3,996,934 and Roseman, et al. 4,308,867 disclose a number of homopolymers, including poly(dimethyl siloxane) and polyurethane, which may be employed individually as the rate controlling means. Arnold U.S. Pat. Nos. 3,961,628 and Zaffaroni 3,993,072 disclose the use of a diffusive medium in the pores of a microporous polymer to control the release of a drug from an inner reservoir. The diffusive medium is permeable to the passage of the drug and is a liquid, a gel, a colloidal suspension or a sol in which the drug has limited solubility. Specific block copolymers have been taught as the rate controlling means in drug release systems. Fildes, et al. U.S. Pat. No. 4,235,988 discloses the use of a linear block copolymer of polyurethane and polyoxyalkylene while Wong U.S. Pat. No. 4,286,587 discloses the use of block copolymer of styrene and butadiene in this service.
Many different types of drugs may be controllably released by means of the prior art systems. The devices disclosed in the Roseman, et al. patent are said to be particularly adapted for lipophilic pharmacological agents. Although the drugs useful in the polymeric devices of the Zaffaroni U.S. Pat. No. '072 are not categorized by their lipophilic or hydrophilic properties but on their particular activity, viz , hypnotics and sedatives, tranquilizers, anticonvulsants, muscle relaxants, hormonal agents, antiparasitic agents, neoplastic agents, etc., the specifically enumerated drugs which can be administered by the disclosed system include primidone and dapsone.
The prior art delivery systems are disclosed as being capable of delivering from 25 nanograms to 25 grams of drug per day (Zaffaroni U.S. Pat. No. '072) as well as 1 to 1.5 grams per day (Leeper, et al. U.S. Pat. No. 3,938,515). Further, the prior art provides formulae and design parameters so that a device employing specific polymers and materials can be designed to provide a desired rate of release of a given drug (see, for example, the Baker, et al. patent and the Leeper, et al. patent). The graphs in the Baker, et al. patent presenting the drug release rate vs. time clearly show that the initial release of drug is substantially higher than that evidenced a short time later. Although this so-called "burst effect" may be considerable or may occasion some unnecessary side-effect, the prior art fails to disclose or suggest that this initial burst effect may be significantly reduced or eliminated.
It is an object of this invention to provide a polymeric device capable of releasing drugs, particularly lipophilic drugs, at a high, sustained, and preferably zero-order, rate for a prolonged period of time.
It is another object of this invention to provide a rate-controlled drug release system which will eliminate or significantly reduce the initial burst effect of drug release, particularly when employed with lipophilic drugs.
It is a further object of this invention to provide a drug release system capable of zero-order rate release of lipophilic drugs, especially phenytoin, primidone and dapsone.
The achievement of these and other objects will be apparent from the following description of the subject invention.